The role of endogenous inhibitors of nitric oxide on glucose homeostasis

• Main Author: Piper, Sophie
• Other Authors: Leiper, James
• Published: Imperial College London 2014
• Subjects: 610
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.656777

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases. ADMA is metabolised by dimethylarginine dimethylaminohydrolase (DDAH) of which there are two isoforms with the same catalytic activity but different tissue expression patterns. Clinically ADMA is relevant as increased levels are seen in multiple pathologies, most notably cardiovascular disease and renal disease. Recent studies have shown increased plasma levels of ADMA in patients with type 2 diabetes and obesity, although these studies did not distinguish between an associative or causal relationship. In human genetic studies, polymorphisms in both DDAH1 and DDAH2 have been associated with type 2 diabetes. Furthermore, mice overexpressing ddah1 have increased insulin sensitivity and overexpression of DDAH2 has been reported to increase insulin secretion from pancreatic β-cell lines. This thesis aims to investigate the relationship between ADMA and the development of insulin resistance and in particular establish whether there is a causal link between elevation of ADMA and the onset of insulin resistance. My work has utilised DDAH deficient mouse strains to mimic loss of DDAH activity and consequent elevation of ADMA. Thorough analysis of glucose homeostasis in global Ddah1 knockout mice by hyperinsulinemic-euglycemic insulin clamp showed no significant dysfunction in insulin sensitivity in these animals. However on a high fat diet, increased ADMA resulted in enhanced adiposity and enhanced insulin resistance compared to fat fed controls. These differences were linked to increased expression of mTOR and SREBP1c in liver tissue and white adipose tissue. Conversely study of Ddah2 knockout animals showed no obvious change in insulin secretion on a normal diet but a marked difference in response to a high fat diet. Ddah2 knockout mice have higher metabolic rates and reduced fat mass compared to fat fed controls. This increased metabolic rate was associated with striking changes in metabolic markers in the brown adipose tissue of Ddah2 knockouts indicating an increase in mitochondrial number and activity. This work suggests that although ADMA does not alone cause insulin resistance it does alter the body's response to a high fat diet that increases the pathology of the condition. This work shows, for the first time, clear and independent roles for DDAH1 and DDAH2, with respect to the control of metabolism and energy expenditure.